This invention relates to methods of treating lung disease, and novel compounds and pharmaceutical compositions useful therefor.
One therapeutic goal in cystic fibrosis and other pulmonary diseases in which the water content of lung mucus is altered is to hydrate the lung mucus secretions, so that the secretions may thereafter be more easily removed from the lungs by mucociliary action or simple coughing. For example, the use of aerosolized amiloride to hydrate mucus secretions is described in U.S. Pat. No. 4,501,729 to Boucher et al. Amiloride appears to block Na+ reabsorption by airway epithelial cells, and therefore inhibits water absorption from the mucus. While an important breakthrough in providing treatments for cystic fibrosis, a potential problem with amiloride as a therapeutic is its relatively short duration of action.
In certain lung diseases (e.g., cystic fibrosis), several functions of airway epithelia are abnormal, and deficiencies in both Clxe2x88x92 transport and Na+ absorption are well documented. See, e.g. Knowles et al., Science 221, 1067 (1983); Knowles et al., J. Clin. Invest. 71, 1410 (1983). Regulation of ion transport is thus thought to have potential therapeutic benefit in lung diseases characterized by abnormalities in epithelial ion transport. Confirmation of the presence of P2Y2 (P2U-purinergic) receptors on the apical surface of human airway epithelial cells raised the possibility that aerosolized nucleotides might be used therapeutically to induce Clxe2x88x92 secretion in individuals with cystic fibrosis or other airway diseases.
Accordingly, a different therapeutic approach for hydrating lung mucus secretions is exemplified by techniques that involve the administration of ATP or UTP, which appear to stimulate chloride secretion from respiratory epithelial cells. See, e.g., U.S. Pat. No. 5,292,498 to Boucher.
Existence of a G-protein-coupled receptor that selectively recognizes uridine 5xe2x80x2-diphosphate (UDP) was originally established in studies of a receptor natively expressed by C6-2B rat glioma cells. E. R. Lazarowski et al. J. Biol. Chem. 269, 11830-11836 (1994). The P2Y6 receptor was recently cloned by K. Chang et al., J. Biol. Chem. 270, 26152-26158 (1995). This receptor was subsequently shown to be selectively activated by UDP, and to be the UDP receptor natively expressed in C6-2B cells. R. A. Nicholas et al., Mol. Pharmacol. 50, 224-229 (1996) The failure to identify this receptor in previous studies of mammalian tissues likely has been a consequence of the lack of availability of potent selective agonists for uridine nucleotide receptors, and the low chemical and metabolic stability of the available nucleotides. It was originally reported that UDP stimulated inositol phosphate accumulation in human airway epithelial cells by low potency activation of the P2Y2 receptor. E. R. Lazarowski et al. Br. J. Pharmacol. 116, 1619-1627 (1995); H. A. Brown et al., Mol. Pharmacol. 40, 648-655 (1991). However, it has been recently demonstrated that UDP is in fact not an agonist at the P2Y2 receptor (Nicholas et al., supra) and that the previously observed effect of UDP at P2Y2 receptors can be explained by the presence of small amounts of contaminating UTP in UDP solutions and/or by conversion of UDP to UTP by cell surface nucleoside diphosphokinase.
Despite the evidence related to the P2Y6 receptor and its relationship to UDP, it has heretofore not been recognized that this relationship may be useful in the treatment of airway disease.
The present inventors have discovered that the P2Y6 receptor, which selectively recognizes UDP as a potent agonist, also exists in airway tissue. The association of the P2Y6 receptor with increases in Clxe2x88x92 secretion indicates that UDP and other receptor-selective drugs that derive from this molecule are of therapeutic value in the treatment of a variety of airway diseases. Accordingly, a first aspect of the present invention relates to a method of hydrating mucus secretions in the lungs of a subject in need of such treatment. The method comprises administering to the lungs of the subject a compound of Formula I below, or a pharmaceutically acceptable salt thereof (hereinafter referred to as the xe2x80x9cactive compoundxe2x80x9d), in an amount effective to hydrate lung mucus secretions: 
wherein:
X1, and X2 are each independently either Oxe2x88x92or Sxe2x88x92;
X3 and X4 are each independently either xe2x80x94H or xe2x80x94OH, with the proviso that X3 and X4 are not simultaneously xe2x80x94H;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene (e.g., dichloromethylene, difluoromethylene);
R2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxyl, nitro and azido;
R3 is selected from the group consisting of H, alkyl, acyl (including arylacyl), and arylalkyl; and
R4 is selected from the group consisting of xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, NRxe2x80x2, and NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, and with the proviso that Rxe2x80x2 is absent when R4 is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring.
The method of the present invention may further comprise the step of concurrently administering amiloride, benzamil, or phenamil to the subject in an amount effective to inhibit the reabsorption of water from lung mucus secretions.
The method of the present invention is usefull in treating several disorders of the lung, including but not limited to, cystic fibrosis, chronic bronchitis, chronic obstructive pulmonary disorder (COPD), primary ciliary dyskinesia, and ventilator-associated pneumonia (VAP).
A second aspect of the present invention is a pharmaceutical composition containing the active compounds disclosed herein, in an amount effective to hydrate lung mucus secretions, in a pharmaceutically acceptable carrier.
Novel compounds useful in the treatment of lung disorders are a third aspect of the present invention. These compounds have the structure of Formula I as set forth above, with the proviso that such novel compounds do not include the known compounds uridine 5xe2x80x2-diphosphate (or UDP), 2-deoxyuridine 5xe2x80x2-diphosphate (or dUDP), uridine 5xe2x80x2-O-(2-thiodiphosphate) (or UDP-xcex2-S), and 4-mercaptouridine 5xe2x80x2-diphosphate (or 4-mercaptoUDP). Novel compounds of the present invention include, but are not limited to, 3xe2x80x2-deoxyuridine 5xe2x80x2-diphosphate; 5-bromouridine 5xe2x80x2-diphosphate; 5-(1-phenylethynyl)-uridine 5xe2x80x2-diphosphate; 5-methyluridine 5xe2x80x2-diphosphate; 4-hexylthiouridine 5xe2x80x2-diphosphate; 4-methoxyuridine 5xe2x80x2-diphosphate; 4-(N-morpholino)uridine 5xe2x80x2-diphosphate; 4-hexyloxyuridine 5xe2x80x2-diphosphate; N,N-dimethylcytidine 5xe2x80x2-diphosphate; N-hexylcytidine 5xe2x80x2-diphosphate; and N-cyclopentylcytidine 5xe2x80x2-diphosphate.
A fourth aspect of the present invention is the use of the active compounds described herein for the manufacture of a medicament for the therapeutic hydration of mucus secretions in the lungs of a subject in need of such treatment.